Thursday, February 5, 2015

Not sure how much this story has been chronicled outside of coverage in the Cancer Letter. Maybe the story has been widely disseminated and I just missed it before.

It is a truly impressive example of integrity. In a nutshell:

1. Duke third year medical student opts to do required third year research project in the lab of a rising star at Duke, Anil Potti. Potti was collaborating with and working under the wing of a another, very prominent Duke faculty member running a large genomics program, Joseph Nevins.

2. Clinical trials were being designed and run--enrolling terminally ill cancer patients--on the basis of Potti's work.

3. The medical student becomes concerned about the research--based on reviewers' comments on a submitted manuscript--and acquires a sophisticated knowledge of the complex topic (analyzing large datasets from genetic studies and identifying markers of tumor susceptibility to specific therapies). His knowledge of the research rapidly advances to the point where he feels comfortable challenging the way the research is being conducted.

4. The student has enough confidence--and courage--to take his concerns up first with Potti and then, up to the next level, with Nevins, and then with the medical school leadership at Duke.

5. Remember, this is a third year medical student doing a required one year research project. He is planning to apply for a competitive residency program and not to go into research. Potti is pressuring the student to get the manuscript out; if not to the journal that is asking questions, then to another one. He has nothing to gain here by making waves and the paper would greatly bolster his chances of landing his desired residency.

6. The student next kicks his concerns up to Duke's associate dean for medical education and its director of student affairs. The former suggests that he reiterate his concerns to Nevins. The student then (March, 2008) writes a nuanced, clear memo of his research concerns. The Cancer Letter states, "According to top-tier biostatisticians who were asked to review these documents, his understanding of biostatistics was extraordinary for a med student—or even for someone with specialized training." Impressive, no?

7. Nevins "implored" the student not to take his concerns any further, according to the Cancer Letter, "because he did not want Duke or any other entity looking closely at the data underlying the clinical trials [that were ongoing and based on Potti's results]."

8. The Cancer Letter says:

Dr. Nevins validated many of Brad Perez’s [the student's] concerns by referring to the serious issues raised regarding Dr. Potti’s lab as “being somewhere along the spectrum between sloppy research and a difference of opinion to research fraud,” and that Dr. Nevins confirmed that he would “go back through each and every dataset that we have posted in relation to various publications to ensure that there are no errors.”

9. The student, having taken his concerns to Potti's sponsor (Nevins) and high up the chain at Duke then moves on.

And get this,

10. He declines to resubmit his first author paper despite co-authorship with and reassurances from prominent Duke faculty members that all was above board and any errors would be fixed

11. The student asks to have his name taken off every other paper from the laboratory--there are a number--on which he is listed as a coauthor.

12. The student returns a merit award he received based on the research in question and turns down an opportunity to present at a major meeting

13. He decides to repeat his third yearof medical school rather than present or publish any results based on the flawed work in the Potti lab

(and all this despite an upcoming application to a competitive residency program)

Epilogue: The student wrote his letter of concern in April, 2008. According to the Cancer Letter, Duke administrators--aware of the letter--met in October 2008 to discuss Potti. Meanwhile, outside experts began to raise concerns. Nevins continued to defend the work and the ongoing clinical trials. Duke allowed the trials to continue.

In 2010 there was a slew of retractions of Potti's work--Lancet Oncology, Nature Medicine, NEJM, etc.--Potti left Duke, and the clinical trials were, late that year, finally halted. In March, 2011, Nevins admits "nonrandom data corruption." The Cancer Letter has discovered that Duke--where Nevins still works--misrepresented its knowledge of the medical student's concerns and put out a false timeline regarding when they became aware of potential problems. Duke is currently being sued by participants in the cancelled trials.

Tuesday, January 20, 2015

The Perspective article details the enormous problems for Obamacare that a win for the plaintiffs in the Supreme Court case King v. Burwell would entail. It is clearly important to proponents of the Affordable Care Act that the plaintiff's case be weak and that the defense prevails. Indeed, the strength of the plaintiff's case is of such great consequence for Obamacare that you would think that the editors would want to see that it was covered fairly.

Here is the sentence regarding the argument at the heart of the case: "The case hinges on enigmatic statutory language that seems to link the amount of tax credits to a health plan purchased 'through an Exchange established by the State.' According to the plaintiffs in King, that language means that consumers who buy insurance through federally run exchanges don't qualify for subsidies"
The authors cannot get around the fact that the law states that only participants in exchanges established by state governments are entitled to subsidies (contrary to how the subsidies are currently being distributed). When the authors say that the wording "seems" to link eligibility for tax credits to buying insurance through a state--rather than the federal--exchange, what they mean is that the law does make that link: they just can't bring themselves to state so plainly, hence the weak attempt to introduce uncertainty.

Of greater interest, the NEJM editors also let the word "enigmatic" slip by. Surely they could have at least provided some hint that the rationale here is not at all enigmatic. Perhaps the best way to understand the rationale is listen to Jonathon Gruber, a key architect of Obamacare, plainly lay the rationale out (lately proponents of the bill have--for obvious reasons--tried to make Gruber's role disappear). Anyone paying attention to the ACA litigation--including the NEJM editors--must be aware of the relevant Gruber videos: they received a lot of attention when they were uncovered. The linkage of subsidies to state exchanges is logical, not mysterious: the purpose is to strongly incentivize states to set up exchanges. Relevant discussions and links to the pertinent Gruber recordings can be readily found through Googling: here is one and another and a third.

Dear NEJM: please think about the balance between functioning as a journal of political advocacy and your general credibility.

Sunday, January 11, 2015

In contrast to the NEJM, the Lancet has long evidenced obvious biases. This has done much to severely damage its credibility. The Journal is run for Elsevier by Jon Horton, who seems to be a man of the European left. His editorial judgments have landed the journal in trouble before. For example, he published two politically-motivated studies from a group at Hopkins purporting to look at deaths in Iraq attributable to US military actions. These studies were later found to be seriouslyflawed and biased by politically-motivated funding.

Worse, though, is Horton's turning what should be a prestigious journal of clinical medicine into a platform for obnoxious anti-Israel propaganda. Recently, as just one example, he discredited himself and his journal by publishing a letter in the middle of the most recent Gaza war authored by a group of viciously anti-Israel activists. Among others, the authors included two who have worked with the former Ku Klux Klan member and current neo-Nazi David Duke and also a maoist, pro-Hamas, strident anti-Israel activist. Later, as the antisemitism underlying the letter became more evident, Horton claimed to be sorry for publishing it. He has yet to remove it from the Lancet's website.

The Lancet reflects poorly on Elsevier and, arguably, on the British medical establishment. Elsevier needs to rethink its staffing of the journal.

Bad:
The New England Journal of Medicine purports to take no position, pro or con, on Obamacare. The Editor-in-Chief and Executive Editor have come out in favor, yet, somehow, despite their biases--they claim--the Journal itself has not staked out a position. This is risible. I subscribe to and very much like the NEJM, but ever since the Affordable Care Act (ACA) was first proposed, the Journal has been flogging Perspectives and other articles written by advocates as if it were a journal of politics and political policy: routinely publishing articles that could just as easily be found on the Op-Ed pages of newspapers or in any number of--primarily left-leaning--political/policy journals. Yes, they have published articles written by skeptics here and there (I can recall only one right now), but basically the Journal has been pushing Obamacare since the get-go: it's not subtle.

No forum for pro-ACA writings would be complete without an essay or two from the egregious Jonathon Gruber. The NEJM's conflict of interest policies has spared the Journal criticism for not disclosing Gruber's financial links to the ACA: if readers took the time and looked closely enough, they could find the NEJM's mandated disclosure (there has typically been no disclosure elsewhere he has been published or quoted). However, I doubt that even NEJM readers who found the disclosures knew at the time of the magnitude of Gruber's financial interests in the ACA. These amounted to millions of dollars: $400,000 from the feds alone. Would the Journal let a consultant being paid millions of dollars by Amgen write a perspective advocating for more Epogen use? If so, would a hard-to-notice financial disclosure statement be adequate, or would perhaps a disclosure need to be included in the text?

One final question: now that we know that Gruber has intentionally obfuscated important facts about Obamacare and has attempted to deceive the Congress and US electorate on key policy points, does the NEJM need to go back and look at his articles? I bet they would have a second look at, say, a clinical trial that was published by an investigator later have found to have published fraudulent manuscripts.

I really like the Journal. It has been painful to see the Journal become so politicized during the ongoing debate surrounding Obamacare. The claim cited above that the Journal has not taken a position is belied by the articles that make it into its pages.

Wednesday, September 10, 2014

I've been on a bit of a hiatus due to a spike in the number of work-related responsibilities and outside matters demanding my time and attention. For example, my wife--the ever-patient Mrs. Grantslave--and I were distracted the last few weeks preparing to ship our oldest child off to college. This bittersweet (for the parents) life-cycle event has now come and gone. I won't drop any clichés about time passing quickly as one gets older, but it does.

I've been linking to reports and editorials concerning biomedical funding issues, and, in this regard, I wanted to be sure to link to this NPR report. It's of interest, first, because of NPR's stature as a national news organization and its influential audience, and, second, because it's well-reported. I was pleasantly surprised, for example, that the report includes a quotation that directs attention towards the large degree of culpability of the biomedical research establishment itself--including the NIH, universities and other major research institutions--for the current gloomy funding environment:

It seemed like great fortune when the NIH budget soared more than a decade ago. "Unfortunately, a lot of research institutions and medical schools were hogs to the trough," Burke says. "They hired a lot of people and built a lot of buildings with the expectation that that would continue. And when that flattened off, and started losing money to inflation, the institutions were essentially bloated."

There was nothing on soft money salaries and how they greatly magnify the impact of funding constraints and the overall level of gloom, but have a look for yourself: the NPR story is a nice, concise introduction for lay people to the current NIH funding situation.

UPDATE: I see now that this story is part of a series by NPR's Richard Harris on the ugly NIH funding environment. The title of the next installment is kind of depressing: When Scientists Give Up. Not sure I want to listen or read the transcript, but the first episode was promising enough that I guess I'll eventually get around to reading the whole series.

Tuesday, August 12, 2014

This comment (written by "William S.") from the discussion of the Physician-Scientist Workforce report on the NIH Rock Talk blog is worth posting because it seconds the point I made in the post immediately prior to this one and perhaps better fleshes out my critique:

From the perspective of the trainee, there are really only two issues relevant to this discussion: career opportunities – (i.e. will I be able to find an appropriate research position when my training is finished?), and career longevity – (i.e. is there a reasonable chance I will still have my lab in 10+ years?). If the answer to either of these questions is no, then attempting to encourage physicians to pursue research careers, through whatever mechanism, is not only misguided but disingenuous. . . . .

If, for whatever reason, the NIH and/or other powers that be feel that current numbers are inadequate for sustaining a robust biomedical work force (and I agree with this assessment) then the focus should not be the individual, but rather system wide, institutional, issues that deter and demoralize highly motivated physicians from choosing this career path. These individuals are generally quite smart and can see the landscape as well as (or perhaps better than) the PSW working group.

Over the last 25 years, 37 percent of Nobel Laureates in Physiology or Medicine had an MD degree.

Over the Lasker Awards’ last 30 years, 41 percent of the Basic Awards and 65 percent of the Clinical Awards have gone to MDs.

69 percent of NIH Institute Directors have an MD degree.

60 percent of the National Academy of Sciences Class IV (Biomedical Sciences) members have an MD degree.

70 percent of the chief scientific officers at the top 10 pharmaceutical companies have an MD degree.

A key focus of the Working Group was determining why the supply of physician-scientists is falling. The uncertainty of grant funding was, not surprisingly, a top concern cited by the students, junior faculty and medical school deans interviewed. Here is a sample of excerpts from the body of the report:

Qualitative research undertaken by and on behalf of the PSW-WG indicated that the uncertainty of funding is by far the biggest concern of young physician-scientist faculty; its importance cannot be overestimated. (page 40; emphasis mine here and below)

The uncertainty of research funding was the major challenge to a career in research articulated by both dual degree students and single degree students interested in pursuing a research career. By far, the largest concern from students interested in research is the issue of funding and the uncertainty of the funding. Job stability is very concerning to those who wish to pursue careers with research components. (page 80)

The [MP/Ph.D.] students admired successful physician-scientists, who are able to continue getting funded for research. . . . On the other hand, these students described the older physician-scientists who are running a lab, being a mentor, and an academic teacher/advisor, as looking tired. Each student in the focus group verbalized that the uncertainty of research funding was the major challenge to a career in research. Financing a career in research and the perceived politics of government funding makes each one nervous about being able to sustain a career as a physician-scientist. (page 91)

Most [MD] students respected and admired those who are physician-scientists, but they were not particularly interested in navigating the grant funding process. . . . “And it is almost like being, to me, how artists have to go out and get gigs and do that whole thing. I feel like researchers have to like go out and find grants, find funding, find people who believe in them, and it just seems really, really tedious.” From a student who has aspirations to do research: “I think the funding environment now is something that is pretty scary."

[Medical school deans] identified the most important factors that they believe influence students’ career decisions. The stability of research funding and ability to sustain a career as a physician-scientist was frequently mentioned as an important factor, since students are observing their professors losing research funding and complaining bitterly about it. (page 111)

Most [young faculty] expressed fear and frustration about the possibility of not being able to continue their research careers if they are not able to secure an R award. They expressed the fear that they have invested so much of their adult life preparing to do scientific research and it could all be ended by not being successful with an R award. They have sacrificed both a lucrative clinical salary, as well as precious time in the hopes of being able to continue to build a research career. (page 117)

Within the body of the report can be found all the key concerns that deter qualified individuals from embarking on a career as a physician-scientist and that threaten the morale of those already engaged in such a career. This leads one to wonder, then, whether whoever devised the list of recommended actions actually read the report.

Trainees contemplating embarking on a career as a physician-scientist and those (like myself) who have already committed to such a career are worried about the overall stability--short-, medium- and long-term--of careers in biomedical science. Incredibly, the recommendations listed at the conclusion of the report are entirely comprised of the standard fare of training programs, fellowships, new investigator privileges etc that we have seen discussed, tested and/or implemented ad nauseum up to now. As before, these all would serve to continue to front-load the pipeline and do not concern what was clearly the chief concern identified: the highly uncertain stability and desirability of physician-scientist positions downstream.

Trainees are not dumb: the report shows that they are not only thinking a year or two or three ahead. They are looking ahead to what happens after that first K award or after they get their first R01: when they are no longer young investigators; perhaps when they have kids, a mortgage, college tuition to pay. The fact that the authors of the recommendations, ignoring the findings presented in the report, think that they can alleviate the shortage of physician-scientists by luring young investigators with goodies up front and hoping that they will forget about increasing pressures, stress and instability downstream is astonishing.

About Me

GrantSlave is a physician-scientist working in academic medicine. He is the product of an inordinately long course of post-graduate education together with a bit of youthful idealism (now mostly gone) and just a hint of masochism. He earned dual M.D.-Ph.D. degrees through the National Institute of Health’s Medical Scientist Training Program. This was followed by internship, residency and then a fellowship with combined subspecialty and research training. He spends most of his work hours running an NIH-funded (for the time being) research program. He also sees patients; teaches medical students, residents and fellows; fills out pages and pages of administrative paperwork; frets about getting his research published and funded; and invests a lot of time convincing himself that the grass is not necessarily greener over the hill.